Oral pulsed dose drug delivery system

ABSTRACT

A multiple pulsed dose drug delivery system for pharmaceutically active amphetamine salts, comprising an immediate-release component and an enteric delayed-release component wherein (1) the enteric release coating has a defined minimum thickness and/or (2) there is a protective layer between the pharmaceutically active amphetamine salt and the enteric release coating and/or (3) there is a protective layer over the enteric release coating. The product can be composed of either one or a number of beads in a dosage form, including either capsule, tablet, or sachet method for administering the beads.

This application is a 371 of PCT/US99/24554 filed Oct. 20, 1999, whichis continuation-in-part of application Ser. No. 09/176,542, filed Oct.21, 1998, now U.S. Pat. No. 6,322,819 the contents of which areincorporated herein by reference.

This invention pertains to a multiple unit dosage form delivery systemcomprising one or more amphetamine salts for administering theamphetamine salts to a recipient.

BACKGROUND OF THE INVENTION

Traditionally, drug delivery systems have focused on constant/sustaineddrug output with the objective of minimizing peaks and valleys of drugconcentrations in the body to optimize drug efficacy and to reduceadverse effects. A reduced dosing frequency and improved patientcompliance can also be expected for the controlled/sustained releasedrug delivery systems, compared to immediate release preparations.However, for certain drugs, sustained release delivery is not suitableand is affected by the following factors:

First pass metabolism: Some drugs, such as β blockers, β-estradiol, andsalicylamide, undergo extensive first pass metabolism and require fastdrug input to saturate metabolizing enzymes in order to minimizepre-systemic metabolism. Thus, a constant/sustained oral method ofdelivery would result in reduced oral bioavailability.

Biological tolerance: Continuous release drug plasma profiles are oftenaccompanied by a decline in the pharmacotherapeutic effect of the drug,e.g., biological tolerance of transdermal nitroglycerin.

Chronopharmacology and circadian rhythms: Circadian rhythms in certainphysiological functions are well established. It has been recognizedthat many symptoms and onset of disease occur during specific timeperiods of the 24 hour day, e.g., asthma and angina pectoris attacks aremost frequently in the morning hours (1,2).

Local therapeutic need: For the treatment of local disorders such asinflammatory bowel disease, the delivery of compounds to the site ofinflammation with no loss due to absorption in the small intestine ishighly desirable to achieve the therapeutic effect and to minimize sideeffects.

Gastric irritation or drug instability in gastric fluid: For compoundswith gastric irritation or chemical instability in gastric fluid, theuse of a sustained release preparation may exacerbate gastric irritationand chemical instability in gastric fluid.

Drug absorption differences in various gastrointestinal segments: Ingeneral, drug absorption is moderately slow in the stomach, rapid in thesmall intestine, and sharply declining in the large intestine.Compensation for changing absorption characteristics in thegastrointestinal tract may be important for some drugs. For example, itis rational for a delivery system to pump out the drug much faster whenthe system reaches the distal segment of the intestine, to avoid theentombment of the drug in the feces.

Pulsed dose delivery systems, prepared as either single unit or multipleunit formulations, and which are capable of releasing the drug after apredetermined time, have been studied to address the aforementionedproblematic areas for sustained release preparations. These same factorsare also problematic in pulsed dose formulation development. Forexample, gastrointestinal transit times vary not only from patient topatient but also within patients as a result of food intake, stress, andillness; thus a single-unit pulsed-release system may give highervariability compared to a multiple unit system. Additionally, druglayering or core making for multiple unit systems is a time-consumingand hard-to-optimize process. Particularly challenging for formulationscientists has been overcoming two conflicting hurdles for pulsatileformulation development, i.e., lag time and rapid release.

Various enteric materials, e.g., cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate,and the EUDRAGIT® acrylic polymers, have been used as gastroresistant,enterosoluble coatings for single drug pulse release in the intestine(3). The enteric materials, which are soluble at higher pH values, arefrequently used for colon-specific delivery systems. Due to theirpH-dependent attributes and the uncertainty of gastric retention time,in-vivo performance as well as inter- and intra-subject variability aremajor issues for using enteric, coated systems as a time-controlledrelease of drugs.

A retarding swellable hydrophilic coating has been used for oral delayedrelease systems (4,5). It was demonstrated that lag time was linearlycorrelated with coating weight gain and drug release was pH independent.

Hydroxypropyl methylcellulose barriers with erodible and/or gellablecharacteristics formed using press coating technology for tablet dosageforms have been described to achieve time-programmed release of drugs(6). Barrier formulation variables, such as grade of hydroxypropylmethylcellulose, water-soluble and water-insoluble excipients,significantly altered the lag time and the release rate from the centercores.

Special grades of hydroxypropyl methylcellulose, e.g., METOLOSE® 60SH,90SH (Shin-Etsu Ltd., Japan), and METHOCEL® F4M (Dow Chemical Company,USA), as a hydrophilic matrix material have been used to achieve bimodaldrug release for several drugs, i.e., aspirin, ibuprofen, and adinazolam(7). Bimodal release is characterized by a rapid initial release,followed by a period of constant release, and finalized by a secondrapid drug release.

Tablets or capsules coated with a hydrophobic wax-surfactant layer, madefrom an aqueous dispersion of carnauba wax, beeswax, polyoxyethylenesorbitan monooleate, and hydroxypropyl methylcellulose have been usedfor rapid drug release after a predetermined lag time. However, eventhough a two-hour lag time was achieved for the model drug theophyllineat a higher coating level (60%), three hours were required for acomplete release of theophylline after the lag time. (8)

A sustained-release drug delivery system is described in U.S. Pat. No.4,871,549. When this system is placed into dissolution medium or thegastrointestinal tract, water influx and the volume expansion of theswelling agent cause the explosion of the water permeable membrane. Thedrug thus releases after a predetermined time period. The OROS®push-pull system (Alza Company) has been developed for pulsatiledelivery of water-soluble and water-insoluble drugs (9,10), e.g. theOROS-CT® system and is based on the swelling properties of an osmoticcore compartment which provides a pH-independent, time-controlled drugrelease.

The PULSINCAP® dosage form releases its drug content at either apredetermined time or at a specific site (e.g., colon) in thegastrointestinal tract (11). The drug formulation is contained within awater-insoluble capsule body and is sealed with a hydrogel plug. Uponoral administration, the capsule cap dissolves in the gastric juice andthe hydrogel plug swells. At a controlled and predetermined time point,the swollen plug is ejected from the PULSINCAP® dosage form and theencapsulated drug is released. A pulsatile capsule system containingcaptopril with release after a nominal 5-hr period was found to performreproducibly in dissolution and gamma scintigraphy studies. However, inthe majority of subjects, no measurable amounts of the drug wereobserved in the blood, possibly due to instability of the drug in thedistal intestine. (12)

ADDERALL® comprises a mixture of four amphetamine salts,dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamineaspartate monohydrate and amphetamine sulfate, which in combination, areindicated for treatment of Attention Deficit Hyperactivity Disorder inchildren from 3-10 years of age. One disadvantage of current treatmentis that a tablet form is commonly used which many young children havedifficulty in swallowing. Another disadvantage of current treatment isthat two separate dose are administered, one in the morning and oneapproximately 4-6 hours later, commonly away from home under other thanparental supervision. This current form of treatment, therefore,requires a second treatment which is time-consuming, inconvenient andmay be problematic for those children having difficulty in swallowingtable formulations.

SUMMARY OF THE INVENTION

Accordingly, in view of a need for successfully administering a multipleunit pulsed dose of amphetamine salts and mixtures thereof, the presentinvention provides an oral multiple unit pulsed dose delivery system foramphetamine salts and mixtures thereof. FIG. 1 illustrates the desiredtarget plasma level profile of the pharmaceutical active containedwithin the delivery system.

In accordance with a preferred embodiment of the present invention,there is provided a pharmaceutical composition for delivering one ormore pharmaceutically active amphetamine salts that includes:

(a) one or more pharmaceutically active amphetamine salts that arecovered with an immediate release coating, and

(b) one or more pharmaceutically active amphetamine salts that arecovered with an enteric release coating wherein (1) the enteric releasecoating has a defined minimum thickness and/or (2) there is a protectivelayer between the at least one pharmaceutically active amphetamine saltand the enteric release coating and/or (3) there is a protective layerover the enteric release coating.

In one embodiment, the immediate release and enteric release portions ofthe composition are present on the same core.

In another embodiment, the immediate release and enteric releasecomponents are present on different cores.

It is also contemplated that the composition may include a combinationof the hereinabove referred to cores (one or more cores that includeboth components on the same core and one or more cores that include onlyone of the two components on the core).

The present invention provides a composition in which there is immediaterelease of drug and enteric release of drug wherein the enteric releaseis a pulsed release and wherein the drug includes one or moreamphetamine salts and mixtures thereof.

The immediate release component releases the pharmaceutical agent in apulsed dose upon oral administration of the delivery system.

The enteric release coating layer retards or delays the release of thepharmaceutical active or drug for a specified time period (“lag time”)until a predetermined time, at which time the release of the drug israpid and complete, i.e., the entire dose is released within about 30-60minutes under predetermined environmental conditions, i.e. a particularlocation within the gastrointestinal tract.

The delay or lag time will take into consideration factors such astransit times, food effects, inflammatory bowel disease, use of antacidsor other medicaments which alter the pH of the GI tract.

In a preferred embodiment, the lag time period is only time-dependent,i.e., pH independent. The lag time is preferably within 4 to 6 hoursafter oral administration of the delivery system.

In one aspect, the present invention is directed to a composition thatprovides for enteric release of at least one pharmaceutically activeamphetamine salt, including at least one pharmaceutically activeamphetamine salt that is coated with an enteric coating wherein (1) theenteric release coating has a defined minimum thickness and/or (2) thereis a protective layer between the at least one pharmaceutically activeamphetamine salt and the enteric release coating and/or (3) there is aprotective layer over the enteric release coating.

In attempting to provide for enteric release of an amphetamine salt,applicants found that use of an enteric release coating as generallypracticed in the art did not provide effective enteric release.

Typical enteric coating levels did not meet the above requirements forthe desired dosage profile of amphetamine salts. Using the typicalamount of enteric coating (10-20μ) resulted in undesired prematureleakage of the drug from the delivery system into the uppergastrointestinal tract and thus no drug delivery at the desired locationin the gastrointestinal tract after the appropriate lag time. Thus thiscoating did not meet the requirements for the drug release profile toprovide full beneficial therapeutic activity at the desired time.

Surprisingly, applicants found that using a thicker application ofenteric coating on the formulation allowed for the second pulsed dose tobe released only and completely at the appropriate time in the desiredpredetermined area of the gastrointestinal tract, i.e., in theintestine.

This was surprising because an increase in thickness of about 5-10μ ofenteric coatings above a minimum thickness of about 10-20μ typicallydoes not have a significant effect on release of drug from within suchcoatings. Enteric coatings typically are pH dependent and will onlydissolve/disperse when exposed to the appropriate environment.Typically, application of a thicker coating (greater than 20μ) will onlymarginally increase the time for complete release at the appropriateenvironmental condition i.e., for a brief period of time (20 minutes).Using the typical coating, applicants could not achieve the desiredresult—rather, the coating leaked before the predetermined time in aninappropriate environment resulting in significant loss of thetherapeutic agent.

Accordingly, in one aspect, the pulsed enteric release of theamphetamine salts is accomplished by employing a certain minimumthickness of the enteric coating.

In one embodiment of the invention, the pulsed dose delivery comprises acomposition which comprises one or more pharmaceutically activeamphetamine salts; an enteric coating over the one or morepharmaceutically active amphetamine salts, wherein the thickness of theenteric coating layer is at least 25μ; a further layer of one or morepharmaceutically active amphetamine salts over the enteric coatinglayer; and an immediate release layer coating. The thicker entericcoating surprisingly provides the required delayed immediate release ofthe pharmaceutically active amphetamine salt at the desired time in thedesired area of the gastrointestinal tract. FIG. 2 illustrates a modelof this delivery system.

In this aspect, the one or more pharmaceutically active amphetaminesalts can be provided within or as a part of a core seed around whichthe enteric coating is applied. Alternatively, a core seed can be coatedwith one or more layers of one or more pharmaceutically activeamphetamine salts.

It has further been discovered that a delayed immediate release drugdelivery can also be accomplished by coating the drug first with aprotective layer prior to applying the enteric coating.

Thus, in another embodiment, the pulsed enteric release is accomplishedby employing a protective layer between the drug and the entericcoating. When using a protective coating, the enteric coating may be ofan increased thickness or may be of lower thickness.

Thus, in another aspect, the object of the invention is met by providinga composition comprising one or more pharmaceutically active amphetaminesalts; a protective layer coating over the one or more pharmaceuticallyactive amphetamine salt layer(s), and an enteric coating layer over theprotective coating layer; a further pharmaceutically active amphetaminesalt layer and an immediate release layer coating. In a preferredembodiment of this aspect, the thickness of the enteric coating is atleast 25μ, and the protective layer comprises an immediate releasecoating.

With respect to this embodiment of the invention, the one or morepharmaceutically active amphetamine salts can be provided within or as apart of a core seed, during the core seed manufacturing process, aroundwhich the protective coating is applied. Alternatively, a core seed canbe coated with one or more layers of one or more pharmaceutically activeamphetamine salts.

In another embodiment, the pulsed enteric release is accomplished byemploying a protective layer over the enteric coating.

Accordingly, in this embodiment of the present invention, there isprovided a pulsed dose release drug delivery system comprising one ormore pharmaceutically active amphetamine salts; an enteric coating layerover the pharmaceutically active amphetamine salt layer(s); and aprotective layer over the enteric coating; a second pharmaceuticallyactive amphetamine salt layer; and an immediate release layer coating.

In one aspect of this embodiment, the protective layer is comprised ofone or more components, which includes an immediate release layer and amodifying layer. The modifying layer is preferably comprised of a semiwater-permeable polymer. Applicants have surprisingly found that asemi-permeable polymer coating used in combination with an immediaterelease layer coating provided a delayed pulsed release drug deliveryprofile when layered over the enteric coating.

Thus, in this embodiment, the protective layer comprises asemi-permeable polymer and an immediate release coating layer. In apreferred embodiment, the modifying layer comprises a first layer of asemi-permeable polymer which is adjacent to the enteric coating layerand a second coating layer over the semi-permeable polymer coating layercomprising an immediate release polymer coating layer.

In one aspect of this embodiment, a semi-permeable polymer, which maycomprise a low water-permeable pH-insensitive polymer, is layered ontothe outer surface of the enteric layer, in order to obtain prolongeddelayed release time. This semi-permeable polymer coating controls theerosion of the pH-sensitive enteric polymer in an alkaline pHenvironment in which a pH-sensitive polymer will dissolve rapidly.Another pH-sensitive layer may be applied onto the surface of a lowwater-permeability layer to further delay the release time.

In a still further aspect of the invention, in addition to a protectivelayer, the composition comprises an acid which is incorporated into thepharmaceutical active layer or coated onto the surface of the activelayer to reduce the pH value of the environment around the entericpolymer layer. The acid layer may also be applied on the outer layer ofthe pH-sensitive enteric polymer layer, followed by a layer of lowwater-permeability polymer. The release of the active thus may bedelayed and the dissolution rate may be increased in an alkalineenvironment.

In a further embodiment, the protective coating may be used both overthe drug and over the enteric coating.

With respect to this embodiment of the invention, the one or morepharmaceutically active amphetamine salts can be provided within or as apart of a core seed, during the core seed manufacturing process, aroundwhich the enteric coating is applied. Alternatively, a core seed can becoated with one or more layers of one or more pharmaceutically activeamphetamine salts.

The drug delivery system of the present invention as described hereinpreferably comprises one or a number of beads or beadlets in a dosageform, either capsule, tablet, sachet or other method of orallyadministering the beads.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a multiple pulse drug delivery system target plasmaprofile of the drug delivery system of the present invention. Theprofile reflects an immediate-release component followed by adelayed-release component.

FIG. 2a graphically illustrates a pulsed dose delivery system.

FIGS. 2b and c graphically illustrate the drug release mechanism fromthe proposed delivery system.

FIG. 3 is a plot of the percent drug released versus time from thedrug-loaded pellets described in Example 1 which exemplifies theimmediate release component of the present invention.

FIG. 4 is a plot of the percent drug released versus time from thecoated pellets described in Example 2 which exemplifies the immediaterelease component and the delayed release components of the presentinvention.

FIG. 5 is a plot of the percent drug released versus time from thecoated pellets of Example 3 which exemplifies the immediate releasecomponent and the delayed release components of the present invention.

FIG. 6 illustrates the drug release profile of coated pellets describedin Example 4 which exemplifies the immediate release component and thedelayed release components of the present invention.

FIG. 7 is a plot of a profile of plasma amphetamine concentration afteradministration of a composite capsule containing the immediate releasepellets and delayed release pellets from Examples 1 and 2, respectively.

FIG. 8 is a plot of a profile of plasma amphetamine concentration afteradministration of a composite capsule containing the immediate releasepellets and delayed release pellets from Examples 1 and 3, respectively.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises a core or starting seed, either preparedor commercially available product. The cores or starting seeds can besugar spheres; spheres made from microcrystalline cellulose and anysuitable drug crystals.

The materials that can be employed in making drug-containing pellets areany of those commonly used in pharmaceutics and should be selected onthe basis of compatibility with the active drug and the physicochemicalproperties of the pellets. The additives except active drugs are chosenbelow as examples:

Binders such as cellulose derivatives such as methylcellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer and the like.

Disintegration agents such as corn starch, pregelatinized starch,cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starchglycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®),and any disintegration agents used in tablet preparations.

Filling agents such as lactose, calcium carbonate, calcium phosphate,calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

Surfactants such as sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate,PLURONIC® line (BASF), and the like.

Solubilizers such as citric acid, succinic acid, fumaric acid, malicacid, tartaric acid, maleic acid, glutaric acid sodium bicarbonate andsodium carbonate and the like.

Stabilizers such as any antioxidation agents, buffers, acids, and thelike, can also be utilized.

Methods of manufacturing the core include

a. Extrusion-Spheronization—Drug(s) and other additives are granulatedby addition of a binder solution. The wet mass is passed through anextruder equipped with a certain size screen. The extrudates arespheronized in a marumerizer. The resulting pellets are dried and sievedfor further applications.

b. High-Shear Granulation—Drug(s) and other additives are dry-mixed andthen the mixture is wetted by addition of a binder solution in a highshear-granulator/mixer. The granules are kneaded after wetting by thecombined actions of mixing and milling. The resulting granules orpellets are dried and sieved for further applications.

c. Solution or Suspension Layering—A drug solution or dispersion with orwithout a binder is sprayed onto starting seeds with a certain particlesize in a fluid bed processor or other suitable equipment. The drug thusis coated on the surface of the starting seeds. The drug-loaded pelletsare dried for further applications.

For purposes of the present invention, the core particles have adiameter in the range of about 50-1500 microns; preferably 100-800microns.

These particles can then be coated in a fluidized bed apparatus with analternating sequence of coating layers.

The core may be coated directly with a layer or layers of at least onepharmaceutically active amphetamine salts and/or the pharmaceuticallyactive amphetamine salt may be incorporated into the core material.Pharmaceutical active amphetamine salts contemplated to be within thescope of the present invention include amphetamine base, all chemicaland chiral derivatives and salts thereof; methylphenidate, all chemicaland chiral derivatives and salts thereof; phenylpropanolamine and itssalts; and all other compounds indicated for the treatment of attentiondeficit hyperactivity disorder (ADHD).

A protective layer may be added on top of the pharmaceutical activecontaining layer and also may be provided between active layers. Aseparation or protective layer may be added onto the surface of theactive-loaded core, and then the enteric layer is coated thereupon.Another active layer may also be added to the enteric layer to deliveran initial dose.

A protective coating layer may be applied immediately outside the core,either a drug-containing core or a drug-layered core, by conventionalcoating techniques such as pan coating or fluid bed coating usingsolutions of polymers in water or suitable organic solvents or by usingaqueous polymer dispersions. Suitable materials for the protective layerinclude cellulose derivatives such as hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer,ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT®RL 30D, OPADRY® and the like. The suggested coating levels are from 1 to6%, preferably 2-4% (w/w).

The enteric coating layer is applied onto the cores with or without sealcoating by conventional coating techniques, such as pan coating or fluidbed coating using solutions of polymers in water or suitable organicsolvents or by using aqueous polymer dispersions. All commerciallyavailable pH-sensitive polymers are included. The pharmaceutical activeis not released in the acidic stomach environment of approximately belowpH 4.5, but not limited to this value. The pharmaceutical active shouldbecome available when the pH-sensitive layer dissolves at the greaterpH; after a certain delayed time; or after the unit passes through thestomach. The preferred delay time is in the range of two to six hours.

Enteric polymers include cellulose acetate phthalate, Cellulose acetatetrimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetatephthalate, carboxymethylethylcellulose, co-polymerized methacrylicacid/methacrylic acid methyl esters such as, for instance, materialsknown under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5,S100 or similar compounds used to obtain enteric coatings. Aqueouscolloidal polymer dispersions or re-dispersions can be also applied,e.g. EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® S100, EUDRAGIT®preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC);KOLLICOAT MAE® 30D and 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

The enteric polymers used in this invention can be modified by mixingwith other known coating products that are not pH sensitive. Examples ofsuch coating products include the neutral methacrylic acid esters with asmall portion of trimethylammonioethyl methacrylate chloride, soldcurrently under the trade names EUDRAGIT® RS and EUDRAGIT® RL; a neutralester dispersion without any functional groups, sold under the tradenames EUDRAGIT® NE30D; and other pH independent coating products.

The modifying component of the protective layer used over the entericcoating can include a water penetration barrier layer (semipermeablepolymer) which can be successively coated after the enteric coating toreduce the water penetration rate through the enteric coating layer andthus increase the lag time of the drug release. Sustained-releasecoatings commonly known to one skilled in the art can be used for thispurpose by conventional coating techniques such as pan coating or fluidbed coating using solutions of polymers in water or suitable organicsolvents or by using aqueous polymer dispersions. For example, thefollowing materials can be used, but not limited to: Cellulose acetate,Cellulose acetate butyrate, Cellulose acetate propionate, Ethylcellulose, Fatty acids and their esters, Waxes, zein, and aqueouspolymer dispersions such as EUDRAGIT® RS and RL 30D, EUDRAGIT® NE 30D,AQUACOAT®, SURELEASE®, cellulose acetate latex. The combination of abovepolymers and hydrophilic polymers such as Hydroxyethyl cellulose,Hydroxypropyl cellulose (KLUCEL®, Hercules Corp.), Hydroxypropylmethylcellulose (METHOCEL®, Dow Chemical Corp.), Polyvinylpyrrolidonecan also be used.

An overcoating layer can further optionally be applied to thecomposition of the present invention. OPADRY®, OPADRY II® (Colorcon) andcorresponding color and colorless grades from Colorcon can be used toprotect the pellets from being tacky and provide colors to the product.The suggested levels of protective or color coating are from 1 to 6%,preferably 2-3% (w/w).

Many ingredients can be incorporated into the overcoating formula, forexample to provide a quicker immediate release, such as plasticizers:acetyltriethyl citrate, triethyl citrate, acetyltributyl citrate;dibutylsebacate, triacetin, polyethylene glycols, propylene glycol andthe others; lubricants: talc, colloidal silica dioxide, magnesiumstearate, calcium stearate, titanium dioxide, magnesium silicate, andthe like.

The composition, preferably in beadlet form, can be incorporated intohard gelatin capsules, either with additional excipients, or alone.Typical excipients to be added to a capsule formulation include, but arenot limited to: fillers such as microcrystalline cellulose, soypolysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose,sucrose, sorbitol, or any other inert filler. In addition, there can beflow aids such as fumed silicon dioxide, silica gel, magnesium stearate,calcium stearate or any other material imparting flow to powders. Alubricant can further be added if necessary by using polyethyleneglycol, leucine, glyceryl behenate, magnesium stearate or calciumstearate.

The composition may also be incorporated into a tablet, in particular byincorporation into a tablet matrix, which rapidly disperses theparticles after ingestion. In order to incorporate these particles intosuch a tablet, a filler/binder must be added to a table that can acceptthe particles, but will not allow their destruction during the tabletingprocess. Materials that are suitable for this purpose include, but arenot limited to, microcrystalline cellulose (AVICEL®), soy polysaccharide(EMCOSOY®), pre-gelatinized starches (STARCH® 1500, NATIONAL® 1551), andpolyethylene glycols (CARBOWAX®). The materials should be present in therange of 5-75% (w/w), with a preferred range of 25-50% (w/w).

In addition, disintegrants are added in order to disperse the beads oncethe tablet is ingested. Suitable disintegrants include, but are notlimited to: cross-linked sodium carboxymethyl cellulose (AC-DI-SOL®),sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), and cross-linkedpolyvinylpolypyrrolidone (Plasone-XL). These materials should be presentin the rate of 3-15% (w/w), with a preferred range of 5-10% (w/w).

Lubricants are also added to assure proper tableting, and these caninclude, but are not limited to: magnesium stearate, calcium stearate,stearic acid, polyethylene glycol, leucine, glyceryl behanate, andhydrogenated vegetable oil. These lubricants should be present inamounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).

Tablets are formed, for example, as follows. The particles areintroduced into a blender along with AVICEL®, disintegrants andlubricant, mixed for a set number of minutes to provide a homogeneousblend which is then put in the hopper of a tablet press with whichtablets are compressed. The compression force used is adequate to form atablet; however, not sufficient to fracture the beads or coatings.

It will be appreciated that the multiple dosage form of the presentinvention can deliver rapid and complete dosages of pharmaceuticallyactive amphetamine salts to achieve the desired levels of the drug in arecipient over the course of about 8 hours with a single oraladministration.

In so doing, the levels of drug in blood plasma of the pharmaceuticallyactive amphetamine salts will reach a peak fairly rapidly after about 2hours, and after about 4 hours a second pulse dose is released, whereina second fairly rapid additive increase of plasma drug levels occurswhich slowly decreases over the course of the next 12 hours.

The following examples are presented to illustrate and do not limit theinvention.

EXAMPLES Example 1 Immediate Release Formulation

The following formulation was used to layer the drug onto sugar spheres.Nonpareil seeds (30/35 mesh, Paulaur Corp., NJ), 6.8 kg were put into aFLM-15 fluid bed processor with a 9″ Wurster column and fluidized at 60°C. The suspension of mixed amphetamine salts (MAS) with 1% HPMC E5Premium (Dow Chemical) as a binder was sprayed onto the seed undersuitable conditions. Almost no agglomeration and no fines were observedwith a yield of at least 98%. The drug-loaded cores were used to testenteric coatings and sustained release coatings.

TABLE 1 Ingredients Amount (%) Nonpareil seed 88.00 mixed amphetaminesalts 11.40 METHOCEL ® E5 Premium 0.60 Water * *removed duringprocessing

The drug release profile of the drug-loaded pellets of this example isshown in FIG. 3.

Example 2

The following formulation was used to coat the mixed amphetamine saltsloaded (MASL) pellets from Example 1 with the EUDRAGIT® L 30D-55 (RohmPharma, Germany) coating dispersion. 2 kg of MASL pellets were loadedinto a fluid bed processor with a reduced Wurster column equipped with aprecision coater (MP 2/3, Niro Inc.). The coating dispersion wasprepared by dispersing Triethyl citrate, Talc and EUDRAGIT® L 30D-55into water and mixing for at least 30 minutes. Under suitablefluidization conditions, the coating dispersion was sprayed onto thefluidized MASL pellets. The spraying was continued until the targetedcoating level was achieved (20μ). The coated pellets were dried at30-35° C. for 5 minutes before stopping the process. The enteric coatedPPA pellets were tested at different pH buffers by a USP paddle method.The drug content was analyzed using HPLC. The results showed that theenteric coating delayed the drug release from the coated pellets untilafter exposure to pH 6 or higher (see Table 2 below). (Reference#AR98125-4)

TABLE 2 Ingredients Amount (%) MASL pellets 40.00 EUDRAGIT ® L 30D-5524.88 Triethyl citrate 2.52 Talc 2.60 Water * *removed during processing

The drug release profile of the coated pellets of this example is shownin FIG. 4.

Example 3

The following formulation was used to coat the MASL pellets from Example1 with the EUDRAGIT® 4110D (Rohm Pharma, Germany) coating dispersion.MASL pellets (2 kg) were loaded in a fluid bed processor with a reducedWurster column (GPGC-15, Glatt). The coating dispersion was prepared bydispersing Triethyl citrate, Talc and EUDRAGIT® 4110D into water andmixing for at least 30 minutes. Under suitable fluidization conditions,the coating dispersion was sprayed onto the fluidized MASL pellets. Thespraying was continued until the targeted coating level was achieved.The coated pellets were dried at 30-35° C. for 5 minutes before stoppingthe process. The enteric coated MASL pellets were tested using a USPpaddle method at different pH buffers. The drug content was analyzedusing HPLC. The enteric coating delayed the drug release for severalhours from the coated pellets until the pH value reached 6.8 or higher,as shown below in Table 3. (Reference #AR98125-3)

TABLE 3 Ingredients Amount (%) MASL pellets 70.00 Eudragit ® 4110D 26.24Triethyl citrate 0.76 Talc 3.00 Water * *removed during processing

The drug release profile of coated pellets of this example is shown inFIG. 5.

Example 4

The following formulation was selected to coat the enteric coated MASLpellets. Coated MASL pellets from Example 2 or coated MASL pellets fromExample 3 (2 kg of either) were loaded into a fluid bed processor with areduced Wurster column (GPGC-15, Glatt). The coating dispersion wasprepared by mixing SURELEASE® (Colorcon) and water for at least 15minutes prior to spraying. Under suitable fluidization conditions, thecoating dispersion was sprayed onto the fluidized pellets. The sprayingwas continued until the targeted coating level was achieved. The coatedpellets were coated with a thin layer of OPADRY® white (Colorcon) (2%)to prevent the tackiness of the coated pellets during storage. Thecoated pellets were then dried at 35-40° C. for 10 minutes beforedischarging from the bed. The drug dissolution from both coated pelletswas performed using a USP paddle method at different pH buffers. Thedrug content was analyzed using HPLC. The 8% SURELEASE® coating slightlysustained the drug release from EUDRAGIT® L 30D-55 coated pellets at pH7.5 buffer, while the SURELEASE® coating delayed the drug release up to2 hours after the buffer switched from pH 1 to pH 7.5. (Reference##AR98125-1)

TABLE 4 Ingredients Amount, (%) Enteric coated MASL pellets 90.00SURELEASE ® 8.00 OPADRY ® white 2.00 Water * *removed during processing

The drug release profile of the coated pellets from this example isshown in FIG. 6.

Example 5

A pulsatile delivery system can be achieved by combining the immediaterelease pellets (Example 1) with delayed release pellets (Example 2 orExample 3). The immediate-release pellets equivalent to half the doseand the delayed-release pellets equivalent to half the dose are filledinto a hard gelatin capsule to produce the oral pulsed dose deliverysystem. The delayed-release portion releases the amphetamine saltsrapidly and completely, after a specified lag time. The capsule productscontaining immediate-release pellets and delayed-release pellets(Example 1 plus Example 2 and Example 1 plus Example 3) were tested in acrossover human study. FIGS. 7 and 8 show the typical profiles of plasmaamphetamine concentration after administration of a composite capsulecontaining the immediate-release pellets and delayed-release pelletsfrom Examples 1 and 2 (10 mg dose each pellet type) and a capsulecontaining the pellets from immediate-release pellets anddelayed-release pellets from Examples 1 and 3 (10 mg dose each pellettype), respectively. The general plasma profiles are similar to thedesired target plasma level profile shown in FIG. 1.

It is to be understood, however, that the scope of the present inventionis not to be limited to the specific embodiments described above. Theinvention may be practiced other than as particularly described andstill be within the scope of the accompanying claims.

CITED LITERATURE

1. B. Lemmer, “Circadian Rhythms and Drug Delivery”, J. ControlledRelease, 16, 63-74 (1991)

2. B. Lemmer, “Why are so many Biological Systems Periodic?” inPulsatile Drug Delivery: Current Applications and Future Trends, RGurny, H E Junginger and N A Peppas, eds. (WissenschaftlicheVerlagsgesellschaft mbH Stuttgart, Germany 1993) pp.11-24

3. X. Xu and P I Lee, “Programmable Drug Delivery from an ErodibleAssociation Polymer System”, Pharm. Res. 10(8), 1144-1152 (1993)

4. A. Gazzaniga, M E Sangalli, and F Giodano, “Oral Chonotropic DrugDelivery Systems: Achievement of Time and/or Site Specificity”, Eur J.Pharm. Biopharm., 40(4), 246-250 (1994)

5. A Gazzaniga, C Busetti, L Moro, M E Sangalli and F Giordano, “TimeDependent Oral Delivery Systems for Colon Targeting”, S.T.P. PharmaSciences 5(1), 83-88 (1996)

6. U Conte, L Maggi, M L Torre, P Giunchedi and A Lamanna, “Press-coatedTablets for Time programmed Release of Drugs”, Biomaterials, 14(13),1017-1023 (1993)

7. A C Shah International Patent Application WO87/00044

8. P S Walia, P Jo Mayer Stout and R Turton, “Preliminary Evaluation ofan Aqueous Wax Emulsion for Controlled Release Coating”, Pharm Dev Tech,3(1), 103-113 (1998)

9. F Theeuwes, “OROS® Osmotic System Development”, Drug Dev Ind Pharm9(7), 1331-1357 (1983)

10. F Theeuwes, “Triggered, Pulsed and Programmed Drug Delivery” inNovel Drug Delivery and its Therapeutic Application, L F Prescott and WS Nimmos, eds. (Wiley, New York, 1989) pp.323-340

11. M McNeil, A Rashid and H Stevens, International Patent AppWO90/09168

12. I R Wilding, S S Davis, M Bakhshaee, H N E Stevens, R A Sparrow andJ Brennan, “Gastrointestinal Transit and Systemic Absorption ofCaptopril from a Pulsed Release Formulation”, Pharm Res 9(5), 654-657(1992)

What is claimed is:
 1. A pharmaceutical formulation for delivery of amixture of amphetamine base salts effective to treat ADHD in a humanpatient comprising: an immediate release dosage form that providesimmediate release upon oral administration to said patient; a delayedenteric release dosage form that provides delayed release upon oraladministration to said patient; and a pharmaceutically acceptablecarrier; wherein said amphetamine base salts comprise dextroamphetaminesulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrateand amphetamine sulfate; wherein said pharmaceutical formulation issufficient to maintain an effective level of amphetamine base salts inthe patient over the course of at least 8 hours without furtheradministration of amphetamine base salt, and the peak plasmaconcentration of amphetamine base salts reached after release of saiddelayed enteric release dosage form exceeds the peak plasmaconcentration previously reached after release of said immediate releasedosage form; and wherein said pharmaceutical formulation, whencontaining about a total dose of 20 mg, will produce in a humanindividual a plasma concentration versus time curve (ng/ml versus hours)having an area under the curve (AUC) of about 467 to about 714 ng hr/ml.2. A formulation of claim 1 wherein said plasma concentration curve hasa maximum concentration (C_(max)) of about 22.5 to about 40 ng/ml forabout a total dose of 20 mg.
 3. A formulation of claim 2 wherein thetime after said oral administration to reach said C_(max) value is about7 to about 10 hours.
 4. A formulation of claim 1 wherein the time aftersaid oral administration to reach maximum concentration of said plasmaconcentration curve is about 7 to about 10 hours.
 5. A formulation ofclaim 2, 3 or 4 wherein said AUC is about 714 ng hr/ml.
 6. A formulationof claim 3 wherein said AUC is about 714 ng hr/ml, the time after saidoral administration to reach said C_(max) value is about 7 hours andC_(max) is about 40 ng/ml.
 7. A formulation of claim 2 wherein C_(max)is about 40 ng/ml.
 8. A formulation of claim 3 or 4 wherein said time isabout 7 hours.
 9. A formulation of one of claims 1-4, 6 or 7 whereinsaid salts are contained in about equal amounts within each of saiddosage forms.
 10. A formulation of one of claims 1-4, 6 or 7 whereinsaid delayed enteric release dosage form comprises a coating of athickness of at least 20 μm which comprises dried about 30% (drysubstance) aqueous dispersion of an anionic copolymer based onmethacrylic acid and acrylic acid ethyl ester, said coating beingsoluble at a pH of about 5.5 upwards.
 11. A formulation of claim 10wherein said thickness is at least 25 μm.
 12. A pharmaceuticalformulation for delivery of a mixture of amphetamine base saltseffective to treat ADHD in a human patient comprising: an immediaterelease dosage form that provides immediate release upon oraladministration to said patient; a delayed enteric release dosage formthat provides delayed release upon oral administration to said patient,wherein said enteric release dosage form comprises a coating of athickness of at least 20 μm which comprises dried aqueous dispersion ofan anionic copolymer based on methacrylic acid and acrylic acid ethylester, said coating being soluble at a pH of about 5.5 upwards; and apharmaceutically acceptable carrier; wherein said amphetamine base saltscomprise dextroamphetamine sulfate, dextroamphetamine saccharate,amphetamine aspartate monohydrate and amphetamine sulfate; wherein saidpharmaceutical formulation is sufficient to maintain an effective levelof amphetamine base salts in the patient over the course of at least 8hours without further administration of amphetamine base salt, and thepeak plasma concentration of amphetamine base salts reached afterrelease of said delayed enteric release dosage form exceeds the peakplasma concentration of said salts previously reached after release ofsaid immediate release dosage form.
 13. A formulation of claim 12wherein said thickness is at least 25 μm.
 14. A formulation of claim 12,wherein said dried aqueous dispersion of an anionic copolymer is a driedabout 30% (dry substance) aqueous dispersion of an anionic copolymer.15. A formulation of claim 1 formulated for a total dose of 20 mg.
 16. Aformulation of claim 2 formulated for a total dose of 20 mg.
 17. Aformulation of claim 1 formulated for a total dose different from about20 mg and having an AUC proportional to said 20 mg AUC.
 18. Aformulation of claim 2 formulated for a total dose different from about20 mg and having a C_(max) proportional to said 20 mg C_(max).